trans

DRUG RESISTANCE IN APICOMPLEXAN PARASITES 403
FIGURE 16.3 Proposed explanation for the transporter-dependent movement of anti-malarial drugs. Chloroquine
(CQ), amodiaquine, and to a lesser extent quinine (QN) interact with free and membrane-bound heme (solid
squares) at an aqueous interface and are substrates for PfCRT (solid circle), which removes drug from the intravacuolar
aqueous space to the parasite cytosol. Mefloquine (MQ) (halofantrine and the artemisinins) and to a lesser
extent quinine interact with membrane-bound heme at the lipid interface and are substrates for Pgh1 (large solid
hexagon amplification) which strips drug from the membrane into the vacuolar sap. Mutations in Pgh1 (small
solid hexagon) preferentially display an increased recognition for mefloquine and halofantrine compared to quinine.
evidence failed to support this hypothesis.
Subsequent studies have attempted to correlate
chloroquine sensitivity with mutations of
pfmdr1. Two pfmdr1 haplotypes have been
identified, the K1 allele carrying an Asn to Tyr
codon change at position 86, and the 7G8 allele
carrying codon changes at positions 184, 1034,
1042 and 1246. Extensive field studies have
failed to clearly link these alleles alone with
chloroquine susceptibility. However, allelic
exchange experiments have demonstrated that
the replacement of the mutations associated
with the 7G8 allele with wild-type sequence
results in an improvement in chloroquine
sensitivity and a reduction in the magnitude
of the verapamil effect, although the parasites
remain phenotypically chloroquine-resistant.
It is suggested that pfmdr1 may act as a modulator
of chloroquine resistance rather than
as a primary determinant (Figure 16.3). This
is supported by the observation that introduction
of the 7G8 mutation into a chloroquinesensitive
genetic background failed to alter
drug susceptibility.
MEDICAL APPLICATIONS